U.S. patent application number 11/050441 was filed with the patent office on 2005-09-01 for new compositions containing quinoline compounds.
This patent application is currently assigned to Active Biotech AB. Invention is credited to Bjork, Anders, Fristedt, Tomas, Jansson, Karl, Wannman, Hans.
Application Number | 20050192315 11/050441 |
Document ID | / |
Family ID | 31885235 |
Filed Date | 2005-09-01 |
United States Patent
Application |
20050192315 |
Kind Code |
A1 |
Jansson, Karl ; et
al. |
September 1, 2005 |
New compositions containing quinoline compounds
Abstract
A stable solid pharmaceutical composition consisting essentially
of an effective amount of a salt of formula (II) 1 together with an
alkaline-reacting component maintaining the pH preferably above 8,
or a salt with a divalent metal cation; and at least one
pharmaceutical excipient; said salt of formula (II) being
essentially stable during storage at room temperature for a period
of at least 3 years. A process for stabilizing the salt of formula
(II). A crystalline salt of formula (II) and a process for
preparing said salt.
Inventors: |
Jansson, Karl; (Dalby,
SE) ; Fristedt, Tomas; (Helsingborg, SE) ;
Wannman, Hans; (Angelholm, SE) ; Bjork, Anders;
(Bjarred, SE) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.
624 NINTH STREET, NW
SUITE 300
WASHINGTON
DC
20001-5303
US
|
Assignee: |
Active Biotech AB
Lund
SE
|
Family ID: |
31885235 |
Appl. No.: |
11/050441 |
Filed: |
February 4, 2005 |
Current U.S.
Class: |
514/312 |
Current CPC
Class: |
A61K 9/2013 20130101;
A61K 9/2059 20130101; A61K 9/2009 20130101; A61K 9/1617 20130101;
A61K 31/4706 20130101; A61K 31/47 20130101; A61P 37/00 20180101;
A61K 9/2054 20130101; A61P 29/00 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/312 |
International
Class: |
A61K 031/4706 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 6, 2004 |
ES |
0400235-8 |
Claims
We claim:
1. A stable solid pharmaceutical composition consisting essentially
of an effective amount of a salt of formula (II) 5wherein n is an
integer of 1, 2 or 3; A.sup.n+ is a mono- or multivalent metal
cation selected from Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.+,
Ca.sup.2+, Mn.sup.2+, Cu.sup.2+, Zn.sup.2+, Al.sup.3+ and
Fe.sup.3+; R is a straight or branched C.sub.1-C.sub.4-alkyl or
-alkenyl or a cyclic C.sub.3-C.sub.4-alkyl; R5 is a straight or
branched, saturated or unsaturated C.sub.1-C.sub.4-alkyl or
-alkenyl, a cyclic C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkylthio, a cyclic C.sub.3-C.sub.4-alkylthio, a
straight or branched C.sub.1-C.sub.4-alkylsulfinyl, a cyclic
C.sub.3-C.sub.4-alkylsulfinyl, fluoro, chloro, bromo,
trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and
R6 taken together are methylenedioxy; R' is hydrogen, a straight or
branched, saturated or unsaturated C.sub.1-C.sub.4-alkyl or
-alkenyl, a cyclic C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkoxy, a cyclic C.sub.3-C.sub.4-alkoxy, fluoro,
chloro, bromo or trifluoromethyl; and P" is hydrogen, fluoro or
chloro, with the proviso that R" is fluoro or chloro only when R'
is fluoro or chloro; an alkaline-reacting component, or a salt with
a divalent metal cation; and at least one pharmaceutical excipient;
wherein said salt of formula (II) is essentially stable during
storage at room temperature for a period of at least 3 years.
2. The solid pharmaceutical composition of claim 1 having a pH
maintained above 8 by the alkaline-reacting component.
3. The solid pharmaceutical composition of claim 1 wherein the salt
of formula (II) is a lithium or calcium salt of
N-ethyl-N-phenyl-5-chloro-1,-
2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide or a
lithium, calcium or zinc salt of
N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1--
methyl-2-oxo-3-quinolinecarboxamide.
4. The solid pharmaceutical composition of claim 1 wherein the salt
of formula (II) is present in an amount of 0.01 to 10% by weight of
the composition.
5. The solid pharmaceutical composition of claim 1 wherein the salt
of formula (II) is present in an amount of 0.1 to 2% by weiglt of
the composition
6. The solid pharmaceutical composition of claim 1 wherein the
alkaline-reacting component is selected from sodium, potassium,
calcium and aluminum salts of acetic acid, carbonic acid, citric
acid and phosphoric acid.
7. The solid pharmaceutical composition of claim 1 wherein the
alkaline-reacting component is present in an amount of 0.1 to 99%
by weight of the composition.
8. The solid pharmaceutical composition of claim 1 wherein the
alkaline-reacting component is present in an amount of 1 to 20% by
weight of the composition.
9. The solid pharmaceutical composition of claim 1 wherein the salt
with a divalent metal cation is calcium acetate.
10. The solid pharmaceutical of claim 9 wherein the calcium acetate
is present in an amount of 1 to 10% by weight of the
composition.
11. The solid pharmaceutical composition of claim 1, wherein the
pharmaceutical excipient is selected from solid powdered carriers,
binders, disintegrants and lubricating agents.
12. The solid pharmaceutical composition of claim 11 wherein the
solid powdered carriers are selected from mannitol,
microcrystalline cellulose, calcium hydrogen phosphate, calcium
sulphate and starch.
13. The solid pharmaceutical composition of claim 11 wherein the
binders are selected from polyvinylpyrrolidone, starch and
hydroxypropyl methylcellulose.
14. The solid pharmaceutical composition of claim 11 wherein the
disintegrants are selected from sodium croscarmellose, sodium
starch glycollate and polyvinylpyrrolidone.
15. The solid pharmaceutical composition of claim 11 wherein the
lubricating agents are selected from magnesium stearate, sodium
stearyl fumarate, talc and hydrogenated vegetable oil.
16. A process for stabilizing a salt of formula (II) 6wherein n is
2; A.sup.n+ is Ca.sup.2+; R is a straight or branched
C.sub.1-C.sub.4-alkyl or -alkenyl or a cyclic C.sub.3-C.sub.4-alkyl
R5 is a straight or branched, saturated or unsaturated
C.sub.1-C.sub.4-alkyl or -alkenyl, a cyclic C.sub.3-C.sub.4-alkyl,
a straight or branched C.sub.1-C.sub.4-alkylthio, a cyclic
C.sub.3-C.sub.4-alkylthio, a straight or branched
C.sub.1-C.sub.4-alkylsulfinyl, a cyclic
C.sub.3-C.sub.4-alkylsulfinyl, fluoro, chloro, bromo,
trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and
R6 taken together are methylenedioxy; R' is hydrogen, a straight or
branched, saturated or unsaturated C.sub.1-C.sub.4-alkyl or
-alkenyl, a cyclic C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkoxy, a cyclic C.sub.3-C.sub.4-alkoxy, fluoro,
chloro, bromo or trifluoromethyl; and R" is hydrogen, fluoro or
chloro, with the proviso that R" is fluoro or chloro only when R'
is fluoro or chloro; by spraying a calcium acetate solution onto a
mixture of the calcium salt of formula (II) and at least one
pharmaceutical excipient, said process giving a salt of formula
(II) which is essentially stable in a solid pharmaceutical
composition during storage at room temperature for a period of at
least 3 years.
17. A process for stabilizing a salt of formula (II) 7wherein n is
an integer of 2 or 3; A.sup.n+ is a multivalent metal cation
selected from Ca.sup.2+, Zn.sup.2+ and Fe.sup.3+; R is a straight
or branched C.sub.1-C.sub.4-alkyl or -alkenyl or a cyclic
C.sub.3-C.sub.4-alkyl; R5 is a straight or branched, saturated or
unsaturated C.sub.1-C.sub.4-alkyl or -alkenyl, a cyclic
C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkylthio, a cyclic C.sub.3-C.sub.4-alkylthio, a
straight or branched C.sub.1-C.sub.4-alkylsulfinyl, a cyclic
C.sub.3-C.sub.4-alkylsulfinyl, fluoro, chloro, bromo,
trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and
R6 taken together are methylenedioxy; R' is hydrogen, a straight or
branched, saturated or unsaturated C.sub.1-C.sub.4-alkyl or
-alkenyl, a cyclic C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkoxy, a cyclic C.sub.3-C.sub.4-alkoxy, fluoro,
chloro, bromo or trifluoromethyl; and R" is hydrogen, fluoro or
chloro, with the proviso that R" is fluoro or chloro only when R'
is fluoro or chloro; by spraying a solution of an alkaline-reacting
component onto a pharmaceutical excipient or a mixture of
pharmaceutical excipients, granulating to proper consistency,
drying the granulate so obtained and mixing the dried granulate
with the salt of formula (II), said process giving a salt of
formula (II) which is essentially stable in a solid pharmaceutical
composition during storage at room temperature for a period of at
least 3 years.
18. A process for stabilizing a salt of formula (II) 8wherein n is
1; A.sup.n+ is a monovalent metal cation selected from Li.sup.+,
Na.sup.+ and K.sup.+; R is a straight or branched
C.sub.1-C.sub.4-alkyl or -alkenyl or a cyclic
C.sub.3-C.sub.4-alkyl; R5 is a straight or branched, saturated or
unsaturated C.sub.1-C.sub.4-alkyl or -alkenyl, a cyclic
C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkylthio, a cyclic C.sub.3-C.sub.4-alkylthio, a
straight or branched C.sub.1-C.sub.4-alkylsulfinyl, a cyclic
C.sub.3-C.sub.4-alkylsulfinyl, fluoro, chloro, bromo,
trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and
R6 taken together are methylenedioxy; R' is hydrogen, a straight or
branched, saturated or unsaturated C.sub.1-C.sub.4-alkyl or
-alkenyl, a cyclic C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkoxy, a cyclic C.sub.3-C.sub.4-alkoxy, fluoro,
chloro, bromo or trifluoromethyl; and R" is hydrogen, fluoro or
chloro, with the proviso that R" is fluoro or chloro only when R'
is fluoro or chloro; by spraying a solution of the compound of
formula (II) and an alkaline-reacting component onto a
pharmaceutical excipient or a mixture of pharmaceutical excipients,
said process giving a salt of formula (II) which is essentially
stable in a solid pharmaceutical composition during storage at room
temperature for a period of at least 3 years.
19. A process for the preparation of a crystalline salt of formula
(II) 9wherein n is an integer of 2 or 3; A.sup.n+ is a multivalent
metal cation selected from Mg.sup.2+, Ca.sup.2+, Mn.sup.2+,
Cu.sup.2+, Zn.sup.2+, Al.sup.3+, and Fe.sup.3+; R is a straight or
branched C.sub.1-C.sub.4-alkyl or -alkenyl or a cyclic
C.sub.3-C.sub.4-alkyl; R5 is a straight or branched, saturated or
unsaturated C.sub.1-C.sub.4-alkyl or -alkenyl, a cyclic
C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkylthio, a cyclic C.sub.3-C.sub.4-alkylthio, a
straight or branched C.sub.1-C.sub.4-alkylsulfinyl, a cyclic
C.sub.3-C.sub.4-alkylsulfinyl, fluoro, chloro, bromo,
trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and
R6 taken together are methylenedioxy; R is hydrogen, a straight or
branched, saturated or unsaturated C.sub.1-C.sub.4-alkyl or
-alkenyl, a cyclic C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkoxy, a cyclic C.sub.3-C.sub.4-alkoxy, fluoro,
chloro, bromo or trifluoromethyl; and R" is hydrogen, fluoro or
chloro, with the proviso that R" is fluoro or chloro only when R'
is fluoro or chloro; by reacting a 3-quinolinecarboxamide
derivative in neutral form or as a sodium salt, with a salt
containing the multivalent metal cation in a liquid phase
consisting of water and at least one water miscible organic
solvent, in which liquid phase the salt of formula (II) is
sparingly soluble.
20. The process of claim 19 wherein the liquid phase is a mixture
of water and ethanol, containing 10-95% ethanol.
21. A crystalline salt of formula (II) 10wherein n is an integer of
2 or 3; A.sup.n+ is a multivalent metal cation selected from
Mg.sup.2+, Ca.sup.2+, Mn.sup.2+, CU.sup.2+, Zn.sup.2+, Al.sup.3+,
and Fe.sup.3+; R is a straight or branched C.sub.1-C.sub.4-alkyl or
-alkenyl or a cyclic C.sub.3-C.sub.4-alkyl; R5 is a straight or
branched, saturated or unsaturated C.sub.1-C.sub.4-alkyl or
-alkenyl, a cyclic C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkylthio, a cyclic C.sub.3-C.sub.4-alkylthio, a
straight or branched C.sub.1-C.sub.4-alkylsulfinyl, a cyclic
C.sub.3-C.sub.4-alkylsulfinyl, fluoro, chloro, bromo,
trifluoromethyl or trifluoromethoxy; and R6 is hydrogen; or R5 and
R6 taken together are methylenedioxy; R' is hydrogen, a straight or
branched, saturated or unsaturated C.sub.1-C.sub.4-alkyl or
-alkenyl, a cyclic C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkoxy, a cyclic C.sub.3-C.sub.4-alkoxy, fluoro,
chloro, bromo or trifluoromethyl; and R" is hydrogen, fluoro or
chloro, with the proviso that R" is fluoro or chloro only when R'
is fluoro or chloro.
Description
FIELD OF THE THE INVENTION
[0001] The present invention relates to stable compositions
containing a salt of a 3-quinoline-carboxamide derivative, to
methods for the manufacture of such a salt and to methods for the
manufacture of a solid pharmaceutical formulation with enhanced
stability during long-term storage at room temperature.
BACKGROUND OF THE INVENTION
[0002] 3-Quinolinecarboxamide derivatives are described in U.S.
Pat. Nos. 4,547,511, 6,077,851, 6,133,285 and 6,121,287. The term
"3-quinolinecarboxamide derivative" as used in this specification
designates the undissociated acid form, hereinafter called the
neutral form, of the compound of formula (I), i.e., the form as
given in the formula (I). 2
[0003] It was unexpectedly found that some 3-quinolinecarboxamide
derivatives in the neutral form disclosed in the above US patents
are susceptible to chemical degradation in solid state, and, in
particular, when in pharmaceutical formulations. Some salts of the
3-quinoline-carboxamide derivatives of formula (I) are known from
said U.S. patents. However, none of the above-mentioned patent
specifications discloses an enabling method of providing
3-quinoline-carboxamide derivatives of formula (I) susceptible to
degradation in a sufficiently stable pharmaceutical form or even
suggests any particular advantage of using the salt form of a
3-quinolinecarboxamide derivative in pharmaceutical
formulations.
SUMMARY OF THE INVENTION
[0004] In accordance with the present invention, there is provided
a stable solid pharmaceutical formulation that contains a salt of a
3-quinolinecarboxamide derivative of formula (I) with a monovalent
or multivalent cation and a process for preparing said formulation.
The process comprises forming a capsule or a tablet containing a
salt of a 3-quinolinecarboxamide derivative and a uniformly
distributed alkaline-reacting component capable of neutralising any
protons dissociating from the excipients, thereby keeping the
3-quinolinecarboxamide in the salt form of formula (II).
[0005] Alternatively, the process comprises forming a capsule or a
tablet containing a salt of a 3-quinolinecarboxamide derivative
sparingly soluble in water and a salt with a divalent metal cation
capable of lowering the dissociation of a salt of formula (II) into
ions.
[0006] The alkaline-reacting component of this invention is
typically sodium carbonate, and the salt with a divalent metal
cation is typically calcium acetate. The solid formulation of the
invention includes pharmaceutical excipients, such as solid
powdered carriers, binders, disintegrants and lubricating
agents.
[0007] The invention additionally provides a process for the
manufacture of a crystalline salt of a 3-quinolinecarboxamide
derivative of formula (I) with a counter ion that is a multivalent
metal cation.
[0008] The present invention solves the problem posed by those
3-quinolinecarboxamide derivatives that are susceptible to chemical
degradation in a solid pharmaceutical formulation.
DESCRIPTION OF THE INVENTION
[0009] Some 3-quinolinecarboxamide derivatives in the neutral form
disclosed in the above U.S. patents are susceptible to chemical
degradation in solid state, and, in particular, when in
pharmaceutical formulations. A primary object of the present
invention is to overcome this stability problem. The solution
offered by the present invention to said stability problem is based
on the surprising and unexpected finding that the salt form of a
compound of formula (I) possesses an enhanced chemical stability
compared to the neutral form of said compound. 3
[0010] The degradation of the compounds of formula (I) was
carefully investigated. The present inventors have demonstrated
that the aniline moiety of the compound of formula (I) unexpectedly
is eliminated and a highly reactive ketene is formed. This ketene
reacts rapidly with, for example, ROH compounds.
[0011] Upon storage without any special precautions being taken,
some 3-quinolinecarboxamide derivatives of formula (I) are degraded
at an unacceptable rate. At storage during accelerated conditions,
that is 40.degree. C. and a relative humidity of 75%, the
degradation of some 3-quinoline-carboxamide derivatives can exceed
2% in a period of 6 months (Table 1). While the rate of
decomposition of 3-quinolinecarboxamide derivatives of formula (I)
at normal storage conditions is lower, it nevertheless is desirable
to obtain a physical form of a 3-quinoline-carboxamide derivative,
which exhibits improved stability.
[0012] Surprisingly and unexpectedly it has now been found that the
3-quinolinecarboxamide derivatives of formula (I), when converted
to a salt form with a mono- or multivalent metal cation of the
structural formula (II), 4
[0013] wherein
[0014] n is an integer of 1, 2 or 3;
[0015] A.sup.n+ is a mono- or multivalent metal cation selected
from Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, Ca.sup.2+, Mn.sup.2+,
Cu.sup.2+, Zn.sup.2+, Al.sup.3+ and Fe.sup.3+;
[0016] R is a straight or branched C.sub.1-C.sub.4-alkyl or
-alkenyl or a cyclic C.sub.3-C.sub.4-alkyl;
[0017] R5 is a straight or branched, saturated or unsaturated
C.sub.1-C.sub.4-alkyl or -alkenyl, a cyclic C.sub.3-C.sub.4-alkyl,
a straight or branched C.sub.1-C.sub.4-alkylthio, a cyclic
C.sub.3-C.sub.4-alkylthio, a straight or branched
C.sub.1-C.sub.4-alkylsu- lfinyl, a cyclic
C.sub.3-C.sub.4-alkylsulfinyl, fluoro, chloro, bromo,
trifluoromethyl or trifluoromethoxy; and
[0018] R6 is hydrogen; or
[0019] R5 and R6 taken together are methylenedioxy,
[0020] R' is hydrogen, a straight or branched, saturated or
unsaturated C.sub.1-C.sub.4-alkyl or -alkenyl or a cyclic
C.sub.3-C.sub.4-alkyl, a straight or branched
C.sub.1-C.sub.4-alkoxy, a cyclic C.sub.3-C.sub.4-alkoxy, fluoro,
chloro, bromo or trifluoromethyl; and
[0021] R" is hydrogen, fluoro or chloro, with the proviso that R"
is fluoro or chloro only when R' is fluoro or chloro;
[0022] have an enhanced stability compared to the corresponding
neutral form of the 3-quinolinecarboxamides of formula (I).
[0023] A preferred group of 3-quinolinecarboxamide salts of formula
(II) are those wherein A.sup.n+ is Li.sup.+, Na.sup.+ and
Ca.sup.2+.
[0024] Another preferred group of 3-quinolinecarboxamide salts of
formula (II) are those salts sparingly soluble in water including
Ca.sup.2+, Zn.sup.2+ and Fe.sup.3+ salts.
[0025] A salt of formula (II) of a 3-quinolinecarboxamide is
prepared by reacting a 3-quinoline-carboxamide of formula (I) with
a mono- or multivalent metal salt. Examples of such salts and
reaction conditions are given below. In general, the aqueous
solubility of salts of formula (II) is higher for the salts with
monovalent cations, e.g., a sodium- or potassium-salt, than for the
salts with multivalent cations, e.g., a calcium, zinc, copper(II)
or iron(III) salt. As an example the sodium salts are readily
soluble in water but they have a limited solubility in less polar
solvents, e.g., chloroform. On the contrary, an iron(III) salt is
almost insoluble in water but has a high solubility in chloroform
and a low solubility in methanol. When using solely aqueous solvent
for the precipitation of a multivalent salt, e.g., a calcium salt
of formula (II), an amorphous precipitate may form because of the
very low solubility in water. However, by increasing the
temperature and by adding a water miscible organic solvent, e.g.,
ethanol, in which the salt has somewhat higher but still a limited
solubility, a crystalline compound can be precipitated. Preferably
mixtures of water and ethanol, containing 10-95% ethanol are used
to ensure crystalline compounds. In such mixtures the particle size
of the precipitate depends on the reaction temperature, the higher
temperature results in larger crystals. The reaction temperature
can vary from 0.degree. C. up to the reflux temperature.
Alternatively, a crystalline salt can be prepared from an amorphous
salt by mixing with a solvent in which the crystalline compound has
a limited solubility as demonstrated in EXAMPLES 4 and 7.
[0026] The storage stability of a compound of formula (II) is
greatly improved. This is evident from a comparison of
N-ethyl-N-phenyl-5-chloro--
1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide
(hereinafter called compound A) with the sodium salt of
N-ethyl-N-phenyl-5-chloro-1,2--
dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide
(hereinafter called compound A sodium). While at 40.degree. C. and
a relative humidity of 75% less than 0.01% of compound A sodium in
solid state is converted to degradation products in a period of 24
months, 0.31% of compound A is degraded during a 6-month period.
Another example of a 3-quinolinecarboxamide derivative susceptible
to degradation is
N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinoline-
carboxamide (hereinafter called compound B), see Table 1.
1TABLE 1 Stability of 3-quinolinecarboxamide derivatives. Storage
conditions: +40.degree. C./75% RH. Compound Degradation.sup.1
"Shelf-life".sup.2 A 0.31% >6 months A sodium <0.01%.sup.3
>6 months B 2.0% <1 months .sup.1Degradation quantified as
the percentage increase of related substances after 6 months of
storage. .sup.2"Shelf life" denotes how long the compound can be
stored at the given conditions without degradation exceeding 0.5%:
.sup.3The same result is obtained after 24 months of storage.
[0027] Generally, any tendency of instability is exacerbated when a
compound of formula (II) is formulated with various excipients.
This is verified by the results from a compatibility study
comparing compound A with compound A sodium shown in Table 2. It is
clear that the salt form is preferred as drug substance in any
binary mixtures of said compound.
2TABLE 2 Compatibility studies comparing compound A with compound A
sodium. The samples are binary mixtures (1:1) of excipient and test
substance. Storage conditions: +40.degree. C./75% RH.
Degradation.sup.1 Degradation.sup.1 (Compound A Excipient (Compound
A) sodium) Microcrystalline Cellulose 1.1% 0.31% (Avicel PH-101)
Maize Starch 0.41% 0.05% Mannitol (Pearlitol 200SD) 0.45% 0.05%
Colloidal silica (Aerosil 200) 20% 1.5% .sup.1Degradation
quantified as the percentage increase of related substances after 6
months of storage.
[0028] Said sodium salt when formulated into conventional solid
pharmaceutical formulation, however, is still degraded at an
unacceptable rate with a level of degradation products exceeding 5%
in 6 months when stored at +40.degree. C. and a relative humidity
of 75% (Table 3). Such a level is considered problematic. An
acceptable limit of degradation, under these conditions, is judged
to be less than 0.5% degradation after 6 months storage. This limit
is considered indicative of a 3-year shelf-life at room
temperature. On the other hand, a conventional solid pharmaceutical
formulation with an alkaline-reacting component also shows an
unacceptable rate of degradation. The crucial step is to obtain a
uniform distribution of the salt of formula (II), the
alkaline-reacting component and all the pharmaceutical excipients
on a molecular level.
3TABLE 3 Stability data from different formulations of compound A
sodium. Degra- Formulation Storage conditions dation.sup.1 "Shelf
life".sup.2 Aqueous solution.sup.3 +2.degree. C. to +8.degree. C.
<0.01% >6 months Conventional tablet +40.degree. C./75% RH
6.8% <0.5 month formulation.sup.4 (reference) Conventional
tablet +40.degree. C./75% RH .sup. 0.64%.sup.7 1 month formulation
with an alkaline-reacting component.sup.5 (reference) EXAMPLE
10.sup.6 +40.degree. C./75% RH 0.16% >6 months (invention)
.sup.1Degradation quantified as the percentage increase of related
substances after 6 months of storage. .sup.2"Shelf life" denotes
how long the formulation can be stored at the given conditions
without degradation exceeding 0.5%. .sup.3Composition: Compound A
sodium 1 mg, sodium hydroxide 0.112 mg, water for injection ad 1
ml, pH adjusted to 7.5. .sup.4Composition: Compound A sodium 0.3 mg
(0.19%), microcrystalline cellulose 49.8%, lactose monohydrate
48.5%, sodium croscarmellose 0.5%, sodium stearyl fumarate 1%.
.sup.5Composition: Compound A sodium 0.3 mg (0.19%), pregelatinised
starch 66%, mannitol 29.8%, sodium carbonate 3.0%, sodium stearyl
fumarate 1.0%. .sup.6Composition: According to EXAMPLE 10.
.sup.7Formation of related substances after 2 months of
storage.
[0029] The present invention provides compositions of a salt form
of a 3-quinolinecarboxamide derivative, such compositions
exhibiting improved storage stability that allows the development
of new pharmaceutical formulations of a 3-quinolinecarboxamide with
enhanced stability during long-term, i.e., at least 3 years,
storage at room temperature.
[0030] Here, the expression a "3-quinolinecarboxamide derivative
susceptible to degradation" should be taken to mean a substance
with a reactivity index >1.0 (see EXAMPLES, Investigation of the
degradation rate below). Mechanistic studies of the ketene
degradation have shown that the degradation involves an
intramolecular transfer of the enol proton in the 4-position of the
quinoline ring to the nitrogen atom of the 3-carboxamide moiety
(Scheme 1). It is envisaged that a stable dosage form of a compound
of formula (I) would be obtained if said compound is converted to
the salt form of formula (II). However, notwithstanding the
enhanced chemical stability of said salt in the solid state, there
still remains an unacceptable degree of instability in conventional
solid dosage forms of the salts of formula (II). The reason for the
instability of salts of formula (II) in conventional solid dosage
forms is now believed to be linked to the exchange of the counter
ion for a proton combined with the conformation of the salt in the
solid state.
[0031] X-ray studies of the sodium salt of compound A demonstrated
that the conformation of the solid salt is such that the exocyclic
carbonyl group is bent away from the enolate oxygen atom in the
4-position. This leads to an open path between the nitrogen atom of
the 3-carboxamide moiety and the enolate sodium atom in the
4-position. Without wishing to be bound to any theory of action, it
is thought that this conformational property of the salts of
formula (II) results in the unacceptable rate of degradation in
conventional solid dosage forms once the counter ion of the salt is
exchanged with a proton obtainable from the excipients.
[0032] From what is said above about the stability properties of
3-quinolinecarboxamide derivatives, it is clear that a stable
dosage form of a compound of formula (I) is obtained when said
compound is present and remains in the salt form of formula (II).
For clinical use a salt of formula (II) of the present invention,
i.e., the active ingredient, suitably is formulated into
pharmaceutical solid formulations for oral mode of administration.
The rigorous prevention of any conversion of said salt to the
neutral form would lead to improved stability of said salts during
manufacture, and during storage of the pharmaceutical formulation.
Examples of such formulations are tablets and capsules. Usually the
amount of active ingredient is about 0.01 to 10% by weight of the
formulation, preferably about 0.1 to 2% by weight of the
formulation.
[0033] Pharmaceutical compositions of the present invention contain
a salt of formula (II) in combination with at least one component
inhibiting degradation of tie active ingredient, and pharmaceutical
excipients. These compositions are one object of this
invention.
[0034] In one embodiment of the present invention, the composition
comprises an alkaline-reacting component, which neutralises the
protons. The amount of the alkaline-reacting component is dependent
upon the property of said alkaline-reacting component and is about
0.1 to 99% by weight of the formulation, preferably about 1 to 20%.
The pH of a specific composition is determined by adding to 2 g of
the composition 4 g of de-ionised water, and then measuring the pH
of the resulting slurry. The pH should preferably be above 8.
Suitable alkaline-reacting components are selected from sodium,
potassium, calcium and aluminum salts of acetic acid, carbonic
acid, citric acid, phosphoric acid, sulphuric acid, or other
suitable weak inorganic or organic acids.
[0035] In another embodiment, the composition comprises a salt with
a divalent metal cation, preferably calcium acetate, and a calcium
salt of formula (II). Any other salt with a divalent metal cation
suitable in view of the intended application of the composition may
be used, e.g., zinc and manganese salts. The amount of said salt is
about 1 to 99% by weight of the formulation depending on the salt
chosen. It is thought that addition of salt containing a divalent
metal cation to the pharmaceutical composition would lower the
dissociation of the salt of formula (II) into ions. A salt of
formula (II) having a divalent metal counter ion has limited
solubility. Thus the protonation of the anion of the salt of
formula (II) is suppressed, which results in an increased
stability.
[0036] Compositions and pharmaceutical formulations containing the
compounds of formula (II) described above are manufactured as
described herein below.
[0037] In the preparation of pharmaceutical formulations in the
form of dosage units for oral administration, the compound (II) is
mixed with a salt with a divalent metal cation or an
alkaline-reacting component and with conventional pharmaceutical
excipients. Suitable excipients can be chosen among, but are not
restricted to, solid powdered carriers, e.g., mannitol,
microcrystalline cellulose, calcium hydrogen phosphate, calcium
sulphate, and starch; binders, e.g., polyvinylpyrrolidone, starch
and hydroxypropyl methylcellulose; disintegrants, e.g., sodium
croscarmellose, sodium starch glycollate and polyvinylpyrrolidone
as well as lubricating agents, e.g., magnesium stearate, sodium
stearyl fumarate, talc and hydrogenated vegetable oil such as
Sterotex NF. The mixture is then processed into tablets or granules
for capsules.
[0038] According to one aspect, the present invention provides a
method of preparing a tablet comprising as an active ingredient a
3-quinolinecarboxamide derivative of improved chemical stability
wherein a tablet core containing a salt of formula (II) and an
alkaline-reacting component, or a salt with a divalent metal
cation, as well as suitable pharmaceutical excipients is
manufactured. The crucial step is to achieve a tablet core with a
uniform distribution, on the molecular level, of the
alkaline-reacting component in order to neutralise all protons
diffusing from the pharmaceutical excipients, or of the salt with a
divalent metal cation in order to suppress the dissociation into
ions of the salt of formula (II).
[0039] Methods of manufacturing a tablet of the invention are as
follows:
[0040] a) a tablet core containing a calcium salt of formula (II)
is manufactured by spraying a calcium acetate solution onto a
mixture of the calcium salt of formula (II) and the pharmaceutical
excipients, granulating the mixture to proper consistency, drying,
and then compressing the granulate; or
[0041] b) a tablet core containing a salt of formula (II) sparingly
soluble in water is manufactured by spraying a solution of an
alkaline-reacting component onto a mixture of the pharmaceutical
excipients, granulating the mixture to proper consistency, drying,
mixing with a crystalline salt of formula (II) sparingly soluble in
water, and then compressing the final blend; or
[0042] c) a tablet core containing a lithium, sodium or potassium
salt of formula (II) is manufactured by spraying a solution of the
salt of formula (II) and an alkaline-reacting component onto a
mixture of the pharmaceutical excipients, granulating the mixture
to proper consistency, drying, and then compressing the granulate;
and
[0043] d) a lubricating agent may optionally be added to the
granulate prior to compression; and
[0044] e) a coating layer is optionally added to said core using
conventional coating pharmaceutical excipients.
[0045] A preferred method of manufacturing a tablet of the
invention is:
[0046] f) a tablet core containing a sodium salt of formula (II) is
manufactured by spraying a solution of a sodium salt of formula
(II) and an alkaline-reacting component onto a mixture of the
pharmaceutical excipients, granulating the mixture to proper
consistency, drying, and then compressing the granulate. A
lubricating agent may optionally be added to the granulate prior to
compression, and a coating layer is optionally added to said core
using conventional coating pharmaceutical excipients.
[0047] According to another aspect, the present invention provides
a method of preparing a capsule comprising as an active ingredient
a 3-quinolinecarboxamide derivative of improved chemical
stability.
[0048] Methods of manufacturing a capsule of the invention are as
follows:
[0049] g) a mixture containing a calcium salt of formula (II) is
manufactured by spraying a calcium acetate solution onto a mixture
of the calcium salt of formula (II) and the pharmaceutical
excipients, granulating the mixture to proper consistency, and
subsequently drying the granulate; or
[0050] h) a mixture containing a salt of formula (II) sparingly
soluble in water is manufactured by spraying a solution of an
alkaline-reacting component onto a mixture of the pharmaceutical
excipients, granulating the mixture to proper consistency, drying
the granulate, and mixing with a crystalline salt of formula (II)
sparingly soluble in water; or
[0051] i) a mixture containing a lithium, sodium or potassium salt
of formula (II), more preferably a sodium salt, is manufactured by
spraying a solution of the salt of formula (II) and an
alkaline-reacting component onto a mixture of the pharmaceutical
excipients, granulating the mixture to proper consistency, and
subsequently drying the granulate;
[0052] j) a lubricating agent is optionally added to the mixture;
and
[0053] k) the final blend is filled into hard gelatine
capsules.
[0054] An alternative method of preparing a salt of formula (II),
which then has to be readily soluble in water is to dissolve the
corresponding compound of formula (I) in the neutral form in a
solution of an alkaline reacting component such as sodium
carbonate, thus producing the salt of formula (II) in-situ, and
subsequently follow the methods as described above.
EXAMPLES
[0055] The examples below are given with the intention to
illustrate the invention without limiting, the scope thereof.
Example 1
Investigation of the Degradation Rate
[0056] The degradation rate, hereinafter called the reactivity
index, of compound of formula (I) was determined in solution.
Roquinimex (Merck Index 12th Ed., No. 8418; Linomide.RTM., LS2616,
N-methyl-N-phenyl-1,2-di-
hydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide) was selected
as a reference compound with the reactivity index defined to 1.0. A
medium of 1-% 0.01M hydrochloric acid in n-propanol was selected.
The reaction temperature was in the range of 45 to 60.degree. C.
The 3-quinolinecarboxamide derivative of formula (I) was added to
the n-propanol solution The reaction transfers the compound to an
n-propylester. The reaction was stopped after 0, 2 and 4 hours, and
analysis was carried out by means of HPLC with UV detection. The
disappearance of the 3-quinolinecarboxamide derivative was used for
evaluation of the reactivity index, but as an alternative also the
formation of the n-propylester may be used. A reactivity index of
1.0 corresponds to a degradation rate of 13% per hour at 60.degree.
C., a reactivity index of 2.0 corresponds to a degradation rate of
26% per hour etc. The reactivity indices of some compounds of
formula (I) are shown in Table 1.
4TABLE 4 Reactivity index of compounds of formula (I). Structure in
relation to compound (I) Compound R5, R6 R', R" R Reactivity index
Roquinimex H H methyl 1.0 (defined) A 5-chloro H ethyl 3.1 B
5-ethyl H ethyl 4.6 C 5-chloro 2,4-F.sub.2 methyl 2.6 D 5-methyl
4-CF.sub.3 methyl >10 E 5,6-methylenedioxy H ethyl 2.9 F
5-methylthio H ethyl >10 Compound A is
N-ethyl-N-phenyl-5-chloro-1,2-d-
ihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide; Compound B
is
N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinol-
inecarboxamide; Compound C is N-methyl-N-(2,4-difluorophenyl)-5-ch-
loro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide;
Compound D is
N-methyl-N-(4-trifluorophenyl)-1,2-dihydro-1,5-dimethyl-4-h-
ydroxy-1-methyl-2-oxo-3-quinolinecarboxamide; Compound E is
N-ethyl-N-phenyl-5,6-methylenedioxy-1,2-dihydro-4-hydroxy-1-methyl-2-oxo--
3-quinolinecarboxamide; and Compound F is N-ethyl-N-phenyl-5-methy-
lthio-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide.
[0057] The following detailed Examples 2 to 7 serve to illustrate
the process for manufacturing the compounds of formula (II), which
are used in the pharmaceutical formulations according to the
present invention.
Example 2
N-Ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinoline-
carboxamide sodium salt
[0058]
N-Ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-qu-
inolinecarboxamide (28 mmol, 10.0 g) was suspended in 99.5% ethanol
(150 ml) and 5 M aqueous sodium hydroxide solution (28.4 mmol, 5.68
ml) was added. The reaction mixture was stirred for 30 minutes at
ambient temperature. The resulting crystalline precipitate was
isolated by filtration, rapidly washed twice with cold ethanol
(2.times.150 ml), and dried in vacuum over P.sub.2O.sub.5 to give
the title compound (9.5 g, 90% yield). Anal. Calcd for
C.sub.19H.sub.16ClN.sub.2O.sub.3Na: C, 60.2; H, 4.26; N, 7.40.
Found C, 60.4; H, 4.20; N, 7.32.
[0059] The solubility in water at room temperature was 13 8
mg/ml.
Example 3
N-Ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinoline-
carboxamide calcium salt
[0060]
N-Ethyl-N-phenyl-5chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-qui-
nolinecarboxamide sodium salt (2.63 mmol, 1.0 g) was dissolved in a
mixture of ethanol (10.5 ml) and water (5.3 ml). The solution was
heated to 70.degree. C. and a solution of calcium acetate hydrate
in water (1M solution, 1.05 eq., 1.38 mmol, 1.38 ml) was added. The
resulting suspension was stirred for 30 minutes, then cooled, and
the crystals were isolated by filtration, washed with water, and
dried under vacuum (966 mg, 98% yield). Anal. Calcd for
C.sub.38H.sub.32Cl.sub.2N.sub.4O.sub.6Ca: C, 60.7; H, 4.29; N,
7.45. Found C, 60.5; H, 4.34; N, 7.41.
[0061] The solubility in water at room temperature was about 1.0
mg/ml. The salt is considered as sparingly soluble in water.
Example 4
N-Ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinoline-
carboxamide iron (III) salt
[0062]
N-Ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-qu-
inolinecarboxamide sodium salt (5.0 g 13.2 mmol) was dissolved in
water (80 ml) at 40.degree. C. and chloroform (100 ml) was added. A
solution of iron(III)sulphate pentahydrate (0.95 eq., 2.09 mmol,
1.023 g) dissolved in water (30 ml) was added. The two-phase system
was stirred vigorously and pH in the aqueous phase was adjusted to
8 with 1 M NaOH. The deep-red organic phase was separated, dried
with sodium sulphate, and solvents were removed to give the title
compound as a red amorphous glassy mass (4.22 g, 85% yield).
MS-ESI: m/z 1122 [MH]+. The glassy mass was dissolved in methanol
and red crystals of the title compound were formed. The crystals
were filtered, washed with methanol, and dried under vacuum to give
the title compound (3.96 g, 80% yield). Anal. Caled for
C.sub.57H.sub.48N.sub.6O.sub.9Cl.sub.3Fe: C, 61.0; H, 4.31; N,
7.48. Found C, 62.7; H, 4.37; N, 7.27. EDTA-titriometric
determination of iron (III) gave a content of 4.90% (theoretical
content is 4.97%).
Example 5
N-Ethyl-N-phenyl-5-ethyl-2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide lithium salt
[0063]
N-Ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-qui-
nolinecarboxamide (4.39 mmol, 1.539 g) was suspended in ethanol
(7.5 ml) and a solution of lithium hydroxide hydrate (1.05 eq. 4.61
mmol, 195 mg) dissolved in water (1.5 ml) was added. The mixture
was stirred for 4 h and ethyl acetate (30 ml) was added. After
stirring for 1 h the crystals were filtered, washed with ethyl
acetate, and dried under vacuum to furnish the title product (1.31
g, 84% yield). Anal. Calcd for C.sub.21H.sub.21N.sub.2O.sub.3Li: C,
70.8; H, 5.94; N, 7.86. Found C, 70.5; H, 5.22; N, 8.01
[0064] The solubility in water at room temperature was 18
mg/ml.
Example 6
N-Ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinec-
arboxamide calcium salt
[0065]
N-Ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-qui-
nolinecarboxamide (5.0 g, 14.2 mmol) was dissolved in a mixture of
1M NaOH (14.26 mmol, 14.26 ml) and ethanol (30 ml), and pH was
adjusted to 7.5. The solution was heated to 70.degree. C. and
calcium acetate hydrate (1.05 eq., 7.5 mmol, 1.335 g) in water (7
ml) was added dropwise during 5 min. The heating was discontinued
and the mixture was stirred at room temperature for 1 h, the
crystals were filtered, washed with ethanol/water 1/l and dried
under vacuum to afford the title compound (5.16 g, 98% yield).
Anal. Calcd for C.sub.42H.sub.42N.sub.4O.sub.6Ca: C, 68.3; H, 5.73;
N, 7.58. Found C, 68.4; H, 5.72; N, 7.63. EDTA-titriometric
determination of calcium gave a content of 5.42% (theoretical
content is 5.42%).
[0066] The solubility in water at room temperature was 0.3
mg/ml.
Example 7
N-Ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinec-
arboxamide zinc salt
[0067]
N-Ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-qui-
nolinecarboxamide (1.0 g, 2.85 mmol) was dissolved in a mixture of
1M NaOH (2.95 mmol, 2.95 ml) and ethanol (6.0 ml). Chloroform (20
ml) and water (40 ml) were added followed by addition of zinc
acetate dihydrate (3.0 mmol, 660 mg). The two-phase mixture was
stirred vigorously for 10 min, the organic phase was separated and
dried with sodium sulphate and the solvents were removed. The
residue was recrystallised from methanol to give the title compound
(823 mg, 76% yield). Anal. Calcd for
C.sub.42H.sub.42N.sub.4O.sub.6Zn: C, 66.01; H, 5.54; N, 7.33. Found
C, 65.4; H, 5.68; N, 7.29. EDTA-titriometric determination of zinc
gave a content of 8.45% (theoretical content is 8.56%).
[0068] The solubility in water at room temperature was 0.3
mg/ml.
Example 8
Description of Manufacturing
[0069] A pharmaceutical formulation according to the present
invention, in the form of capsules, having the following
composition was prepared:
5 Granulate 0.17% Solid excipients Mannitol 96.8% Sodium carbonate
3.00% Granulation fluid Compound A sodium.sup.1 0.18% Sodium
carbonate 0.03% Water (13.3% of solid excipients) na.sup.2 Capsules
Final blend Compound A sodium Granulate 0.17% 99.0% Sodium stearyl
fumarate 1.00% .sup.1The compound given above may be replaced with
another compound of the present invention. .sup.2The water is
removed during drying.
[0070] Compound A sodium was dissolved in aqueous sodium carbonate
and wet granulated together with mannitol and additional sodium
carbonate. All excipients required for capsule filling except the
lubricant were present in the granulation step. The resulting
granulate was dried in a conventional manner and passed through a
screen of suitable size. The dry granules were mixed well with
sodium stearyl fumarate and the mixture obtained was filled into
capsules. The capsules contained suitable amounts of the active
ingredient.
Example 9
Description of Manufacturing
[0071] A pharmaceutical formulation according to the present
invention, in the form of capsules, having the following
composition was prepared:
6 Granulate 0.18% Solid excipients Compound B calcium.sup.1 0.19%
Mannitol 65.0% Microcrystalline cellulose 32.0% Granulation fluid
Calcium acetate 3.00% Water (50.0% of solid excipients) na.sup.2
.sup.1The compound given above may be replaced with another
compound of the present invention. .sup.2The water is removed
during drying.
[0072] A preblend of compound B calcium, mannitol and
microcrystalline cellulose was prepared. The preblend was wet
granulated with am aqueous calcium acetate solution. All excipients
required for capsule filling were present in the granulation step.
The resulting granulate was dried in a conventional manner and
passed through a screen of suitable size. The dry granules were
filled into capsules. The capsules contained suitable amounts of
the active ingredient
Example 10
Description of Manufacturing
[0073] A pharmaceutical formulation according to the present
invention, in the form of tablets, having the following composition
was prepared:
7 Granulate 0.19% Solid excipients Mannitol 30.0% Pregelatinised
starch 66.8% Sodium carbonate 2.84% Granulation fluid Compound A
sodium.sup.1 0.20% Sodium carbonate 0.20% Water (35.8% of solid
excipients) na.sup.2 Tablets Compound A sodium Granulate 0.19%
93.1% Sodium stearyl fumarate 0.94% Coating suspension Opadry
03B28796 White 6.00% .sup.1The compound given above may be replaced
with another compound of the present invention. .sup.2The water is
removed during drying.
[0074] Compound A sodium was dissolved in aqueous sodium carbonate
and wet granulated together with mannitol, pregelatinised starch
and additional sodium carbonate. All excipients required for
tabletting except the lubricant were present in the granulation
step. The resulting granulate was dried in a conventional manner
and passed through a screen of suitable size. The dry granules were
mixed well with sodium stearyl fumarate and the mixture obtained
was compressed to tablets. The tablets were coated with a film on
Opadry 03B28796 White. The tablets contained suitable amounts of
the active ingredient.
Example 11
Description of Manufacturing
[0075] A pharmaceutical formulation according to the present
invention, in the form of tablets, having the following composition
was prepared:
8 Granulate 0.18% Solid excipients Mannitol 32.0% Macrocrystalline
cellulose 65.8% Granulation fluid Compound A sodium.sup.1 0.20%
Sodium carbonate 0.20% Sodium hydrogen carbonate 1.80% Water (50.0%
of solid excipients) na.sup.2 Tablets Compound A sodium Granulate
0.18% 99.0% Sodium stearyl fumarate 1.00% .sup.1The compound given
above may be replaced with another compound of the present
invention. .sup.2The water is removed during drying.
[0076] Compound A sodium was dissolved in aqueous solution of a
sodium carbonate/sodium hydrogen carbonate mixture and wet
granulated together with mannitol and microclystalline cellulose.
All excipients required for tabletting except the lubricant were
present in the granulation step. The resulting granulate was dried
in a conventional manner and passed through a screen of suitable
size. The dry granules were mixed well with sodium stearyl fumarate
and the mixture obtained was compressed to tablets. The tablets
contained suitable amounts of the active ingredient.
Example 12
Description of Manufacturing
[0077] A pharmaceutical formulation according to the present
invention, in the form of tablets, having the following composition
was prepared:
9 Granulate 0.18% Solid excipients Mannitol 48.5% Calcium sulphate
dihydrate 48.3% Sodium carbonate 3.02% Granulation fluid Compound A
sodium.sup.1 0.19% Sodium carbonate 0.01% Water (6.7% of solid
excipients) na.sup.2 Tablets Compound A sodium Granulate 0.18%
99.0% Sodium stearyl fumarate 1.00% .sup.1The compound given above
may be replaced with another compound of the present invention.
.sup.2The water is removed during drying.
[0078] Compound A sodium was dissolved in aqueous sodium carbonate
solution and wet granulated together with mannitol, calcium
sulphate dihydrate and additional sodium carbonate. All excipients
required for tabletting except the lubricant were present in the
granulation step and the resulting granule was dried in a
conventional manner. The dry granules were mixed well with sodium
stearyl fumarate and the mixture obtained was compressed to
tablets. The tablets contained suitable amounts of the active
ingredient.
* * * * *